Morphinan-6-ones are important synthetic intermediates to many opium alkaloid compounds including buprenorphine, codeine, diacetylmorphine, dihydrocodeine, dihydroetorphine, diprenorphine, etorphine, hydrocodone, hydromorphone, morphine, nalbuphene, nalmefene, naloxone, naltrexone, oxycodone, and oxymorphone. Generally, these compounds are analgesics, which are used extensively for pain relief in the field of medicine due to their action as opiate receptor agonists. However, nalmefene, naloxone, and naltrexone are opiate receptor antagonists; and are used for reversal of narcotic/respiratory depression due to opiate receptor agonists.
Various processes for the total synthesis of morphinan-6-ones such as through the intermediate nordihydrothebaineone are known. In U.S. Pat. Nos. 4,368,326 and 4,521,601, for example, Rice discloses the N-formylation of a tetrahydroisoquinoline using ethyl formate or phenyl formate, respectively. Rice further discloses reacting the tetrahydroisoquinoline with ethylene glycol, and brominating the resulting ketal. After removing the ketal protecting group to form a bromoketone, Rice prepares a nordihydrothebaineone (e.g., 1-(2′-bromo-4′-methoxy-5′-hydroxybenzyl)-2-formyl-1,3,4,5,7,8-hexahydroisoquinolin-6-one) from the bromoketone by Grewe cyclization catalyzed using a super acid medium alone or with a combination of an ammonium fluoride complex and hydrogen fluoride or trifluoromethanesulfonic acid.
The presence of water and other contaminants in the reaction mixtures of various synthetic steps employed in the formation of morphinan-6-ones and analogs and intermediates thereof is one factor that affects the reproducibility and yields of such steps. Contaminants in the starting β,γ-hexahydroisoquinoline reaction mixture used in the Grewe cyclization, for example, cause reproducibility problems and low yields of the desired cyclized products.
Although the techniques of Rice and others are generally useful for the preparation of various morphinan-6-ones and salts, intermediates, and analogs thereof, there are limitations to their effectiveness and/or efficiency including, for example, the crystallization and re-solubilization of intermediate compounds, material losses in crystallization and transfer, relatively lengthy reaction times, and an increased likelihood of impurities and/or by-product formation. As a result of the higher level of impurities and/or by-products, lower yields of the cyclized morphinan-6-one product are obtained. Accordingly, a need remains for additional processes for the preparation of morphinan-6-ones and salts, intermediates, and analogs thereof having improved reaction times, product yields, and fewer impurities and/or by-products.